5-Oxa phenyl-and phenoxy-substituted prostaglandin F{HD 1{301 {0 {B analogs

ABSTRACT

5-Oxa phenyl- and phenoxy-substituted prostaglandin-type compounds and processes for making them. These compounds are useful for a variety of pharmacological purposes, including antiulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

United States Patent Nelson 51 Feb. 4, 1975 4] S-OXA PHENYL-AND [56]References Cited JIFENQZ HHE IE EQ FOREIGN PATENTS OR APPLICATIONSPROSTAGLANDIN ANALOGS 7,306,462 11/1973 Netherlands 260/468 Inventor:Nqrman A. Nelson, Galesburg 2,165,184 Germany 260/468 Mlch- OTHERPUBLICATIONS [73] Assignee: The Upjohn Company, Kalamazoo, Nakano,Prostaglandins, p. 26 (197) (1973).

Mich. Primary Examiner-Robert Gerstl [22] May 1973 Attorney, Agent, orFirm-Morris L. Nielsen [21] Appl. N0.: 361,990

[57] 7 ABSTRACT 52 s Cl N A, 2 0 21 1 R, 2 0 2472 R, 5-OX8 phenylandphenoxy-substituted prostaglandin- 260/268 B 260/243 65 260/326 3 typecompounds and processes for makmg them. 260/345 8 mo/3459 260/343 2These compounds are useful for a variety of pharma- 260/346i 260/424'9cological purposes, including anti-ulcer, inhibition of 260/448 2'60/4682'60/448 8 platelet aggregation, increase of nasal patency, labor260/473 B, 260/50l .'1. 260/50l.l5: inducement at term, and woundhealing. 260/501.l7, 260/5012, 260/51 1.1 D, 260/520 22 Claims, NoDrawings [51] Int. Cl... C07c 61/32, C07c 63/60, C07c 69/71 [58] Fieldof Search 260/468 D, 514 D, 473 S,

S-OXA PHENYL-AND PHENOXY-SUBSTITUTED PROSTAGLANDIN F ANALoGs BACKGROUNDOF THE INVENTION This invention relates to novel compositions of matter,to novel methods for producing those, and to novel chemicalintermediates useful in those processes. Particularly, this inventionrelates to certain novel analogs of prostaglandins E F R A,, and B inwhich the C-5 methylene (-CH in the prostanoic acid to structure isreplaced by oxygen The known prostaglandins include, for example.prostaglandin E (PGE prostaglandin F, alpha and beta (PGF and PGF, 5prostaglandin A, (PG/X and prostaglandin B (PGB,). Each of theabovementioned known prostaglandins is a derivative of prostanoic acidwhich has the following structure and atom numbering:

See, for example, Bergstrom et al.. Pharmacol, Rev. 20, l (l968), andreferences cited therein. A systematic name for prostanoic acid is7-[(2B-octyl)-cyclopentla-yl ]-heptanoic acid.

PGE, has the following structure:

/ Ill PGH has the following structure:

FOB, has the following structure:

ln formulas ll to Vl, as well as in the formulas given hereinafter.broken line attachments to the cyclopentane ring indicate substituentsin alpha configuration. i.e., below the plane of the cyclopentane ring.Heavy solid line attachments to the cyclopentane ring indicatesubstituents in beta configuration. i.e., above the plane of thecyclopentane ring.

The side-chain hydroxy at C-l5 in formulas II to VI is in Sconfiguration. See Nature. 212. 38 (1966) for discussion of thestereochemistry of the prostaglandins.

Molecules of the known prostaglandins each have several centers ofasymmetry, and can exist in racemic (optically inactive) form and ineither of the two enantiomeric (optically active) forms, i.e. thedextrorotatory and levorotatory forms. As drawn, formulas [I to VI eachrepresent the particular optically active form of the prpostaglandinwhich is obtained from certain mammalian tissues, for example, sheepvesicular glands, swine lung, or human seminal plasma, or by carbonyland/or double bond reduction of that prostaglandin. See, for example,Bergstrom et al., cited above. The mirror image of each of formulas [Ito Vl represents the other enantiomer of that prostaglandin. The racemicform of a prostaglandin contains equal numbers of both enantiomericmolecules, and one of formulas ll to V1 and the mirror image of thatformula is needed to represent correctly the corresponding racemicprostaglandin. For convenience hereinafter, use of the terms, PGE PGFPGF and the like, will mean the optically active form of thatprostaglandin with the same absolute configuration as PGE, obtained frommammalian tissues. When reference to the racemic form of one of thoseprostaglandins is intended, the word racemic or dl" will preceed theprotaglandin name, thus, racemic PGE or dl-PGF I PGE PGF PGF,B PGA, andPGE and their esters, acylates, and pharmacologically acceptable salts,are extremely potent in causing various biological responses. For thatreason, these compounds are useful for pharmacological purposes. See,for example, Bergstrom et aL, cited above. A few of those biological responses are systemic arterial blood pressure lowering in the case ofthePGE and PGA compounds as measured, for example, in anesthetized(pentobarbital sodium) pentolinium-treated rats with indwelling aorticand right heart cannulas; pressor activity, similarly measured, for thePGF compounds; stimulation of smooth muscle as shown, for example, bytests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon;potentiation of other smooth muscle stimulants; antilipolytic activityas shown by antagonism of epinephrine-induced mobilization of free fattyacids or inhibition of the spontaneous release of glycerol from isolatedrat fat pads; inhibition or gastric secretion in the case of the PGE andPGA compounds as shown in dogs with secretion stimulated by food orhistamine infusion; activity on the central nervous system; controllingspasm and facilitating breathing in asthmatic conditions; decrease ofblood platelet adhesiveness as shown by platelet-to-glass adhesiveness,and inhibition of blood platelet aggregation and thrombus formationinduced by various physical stimuli, e.g., arterial injury;

and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin,and collagen; and in the case of the PGE and PCB compounds, stimulationof epidermal proliferation and keratinization as shown when applied inculture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in adose range of about 10 ug. to aboutl mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE, PGF PGFB and PGA compounds are useful in the treatment ofasthma. For example, these compounds are useful as bronchodilators or asinhibitors or mediators, such as SRS-A, and histamine which are releasedfrom cells activated by an antigenantibody complex. Thus, thesecompounds control spasm and facilitate breathing in conditions such asbronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema.For these purposes, these compounds are administered in a variety ofdosage forms, e.g., orally in the form of tablets, capsules, or liquids;rectally in the form of suppositories, parenterally, subcutaneously, orintramuscularly, with intravenous administration being preferred inemergency situations; by inhalation in the form of aerosols os solutionsfor nebulizers; or by insufflation in the form of powder. Doses in therange of about 0.01 to mg. per kg. of body weight are used 1 to 4 timesa day, the exact dose depending on the age, weight, and condition of thepatient and on the frequency and route ofadministration. For the aboveuse these prostaglandins can be combined advantageously with otheranti-asthmatic agents, such as sympathomimetics (isoproterenol,phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline andaminophyllin); see South corticosteroids (ACTH and prednisolone).Regarding. use of these compounds see African Pat. No. 68/l055.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce and controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose.the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 #g. to about 500.Lg. per kg. of body weight per minute, or in a total daily dose byinjection or infusion in the range about 0.1 to about mg. per kg. ofbody weight per day, the exact dose depending on the age, weight, andcondition of the patient of animal, and on the frequency and route ofadministration.

The PGE. PGF and PGF compounds are useful whenever it is desired toinhibit platelet aggregation, to reduce the adhesive character ofplatelets, and to remove or prevent the formation of thrombi in mammals,

including man, rabbits, and rats. For example, these compounds areuseful in the treatment and prevention of myocardial infarcts. to treatand prevent postoperative thrombosis, to promote patency of vasculargrafts following surgery, and to treat conditions such asatherosclerosis. arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inemergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGF ,and PGF compounds are especially useful as additives toblood, blood products. blood substitutes, and other fluids which areused in artificial extracorporeal circulation and perfusion of isolatedbody portions, e.g., limbs and organs, whether attached to the originalbody, detached and being preserved or prepared for transplant, orattached to the new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state doseofabout 0.00l to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g:, cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly ac tive in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE for example, is useful in place of or in combination withless than usual amounts of these known smooth muscle stimulators, forexample, to relieve the symptoms of paralytic ileus, or to control orprevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.0]to about 50 pg. per kg. of body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.0l to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE and PGA compounds are useful as hypotensive agents to reduceblood pressure in mammals, including man. For this purpose, thecompounds are administrered by intravenous infusion at the rate of about0.01 to about 50 pg. per kg. of body weight per minute, or in single ormultiple doses of about 25 to 500 pg. per kg of body weight total perday.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especially in cases of severelyimpaired renal blood flow, for example, the hepatorenal syndrome andearly kidney transplant rejection. In cases of excessive orinappropriate ADH (antidiuretic hormone; vasopressin) secretion, thediuretic effect of these compounds is even greater. In anephric states,the vasopressin action of these compounds is especially useful.lllustratively, the PGA compounds are useful to alleviate and correctcases of edema resulting, for example, from massive surface burns, andin the management of shock. For these purposes, the PGA compounds arepreferably first administered by intravenous injection at a dose in therange l0 to 1000 .tg. per kg. of body weight or by intravenous infusionat a dose in the range 0.1 to pg per kg. of body weight per minute untilthe desired effect is obtained. Subsequent doses are given byintravenous, intramuscular, or subcutaneous injection or infusion in therange 0.05 to 2 mg. per kg. of body weight per day.

The PGE, PGF and PGFB compounds are useful in place of oxytocin toinduce labor in pregnant female animals, including man, cows, sheep, andpigs, at or near term, or in pregnant animals with intrauterine deathofthe fetus from about 20 weeks to term. For this purpose, the compoundis infused intravenously at a dose of 0.01 to 50 pg. per kg. of bodyweight per min ute until or near the termination of the second stage oflabor, i.e., expulsion of the fetus. These compounds are especiallyuseful when the female is one or more weeks post-mature and naturallaborhas not started, or 12 to 60 hours after the membranes haveruptured and natural labor has not yet started. An alternative route ofadministration is oral.

The PGF and PGF 3 compounds are useful for controlling the reproductivecycle in ovulating female mammals, including humans and animals such asmonkeys, rats, rabbits, dogs, cattle, and the like. By the termovulating female mammals is meant animals which are mature enough toovulate but not so old that regular ovulation has ceased. For thatpurpose, PGF for example, is administered systemically at a dose levelin the range 0.01 mg. to about 20 mg. per kg. of body weight of thefemale mammal, advantageously during a span of time startingapproximately at the time of ovulation and ending approximately at thetime of menses or just prior to menses. lntravaginal and intrauterineare alternative routes of administration. Additionally, expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the normal mammalian gestationperiod.

The PGE and PGF compounds are useful in causing cervical dilation inpregnant and nonpregnant female mammals for purposes of gynecology andobstetrics. In labor induction and in clinical abortion produced bythese compounds, cervical dilation is also observed. In cases ofinfertility, cervical dilation produced by PGE and PGF compounds isuseful in assisting sperm movement to the uterus. Cervical dilation byprostaglandins is also useful in operative gynecology such as D and C(Cervical Dilation and Uterine Curettage) where mechanical dilation maycause perforation of the uterus, cervical tears, or infections. lt isalso useful in diagnostic procedures where dilation is necessary fortissue examination. For these purposes, the PGE and PGF compounds areadministered intramuscularly or subcutaneously at doses of about one to25 mg. per treatment. The exact dosages for these purposes depend on theage, weight, and condition of the patient or animal.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,these compounds are useful in experimental medicine for both in vitroand in vivo studies in mammals, including man, rabbits. and rats,intended to lead to the understanding, prevention, symptom alleviation,and cure ofdiseases involving ab normal lipid mobilization and high freefatty acid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGB compounds promote and accelerate the growth of epidermal cellsand keratin in animals. including humans, useful domestic animals, pets,zoological specimens, and laboratory animals. For that reason, thesecompounds are useful to promote and accelerate healing of skin which hasbeen damaged, for example, by burns, wounds, and abrasions, and aftersurgery. These com pounds are also useful to promote and accelerateadherence and growth of skin autografts, especially small, deep (Davis)grafts which are intended to cover skinless areas by subsequent outwardgrowth rather than initially, and to retard rejection of homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separately or in combination with the usual infusions of blood, plasma,or substitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject.Especially for topical use, these prostaglandins are useful incombination with antibiotics, for example, gentamycin, neomycin,polymyxin B, bacitracin, spectinomycin, and oxytetracyline, with otherantibacterials, for example, mafenide hydrochloride, sulfadiazine,furazolium chloride, and nitrofurazone, and with corticoid steroids, forexample, hydrocortisone, prednisolone, methylprednisolone, andfluprednisolone, each of those being used in the combination at theusual concentration suitable for its use alone.

Several related compounds have been reported in the literature.dl-3-Oxa-PGE,, dl-3-oxa-PGF and dl-3- oxa-PGA all as ethyl esters, weredescribed by G. Bundy et al., Ann. N.Y. Acad. Sci. 180, 76 (1971). Seealso German Offenlegungsschrift P 2,036,471, Feb. l l, 1971, referencein Derwent No. 10,044S-B. l5-Deoxy- 7-oxa-PGE and 7-oxa-l Sa/B-PGE, werereported by .l. Fried et al., Tetrahedron Lett. 2695 (1970).

SUMMARY OF THE INVENTION It is a purpose of this invention to providenovel S-oxa prostagalandin E, F. A, and B analogs. It is a furtherpurpose to provide novel S-oxa prostaglandin analogs with a varietyofsubstituents and degrees of saturation in the side chains. It is afurther purpose to provide -oxa prostaglandin analogs having the ll-deoxy ringstructure in which the l l-hydroxy is replaced by hydrogen.lt is a further purpose to provide esters, lower alkanoates, andpharmacologically acceptable salts of said analogs. It is a furtherpurpose to provide novel processes for preparing said analogs andesters. It is still a further purpose to provide novel intermediatesuseful in said processes.

The novel prostaglandin analogs of this invention each have an oxygen O)in place of the methylene (CH moiety at the 5-position of the prostanoicacid formula. They are represented by the generic formula wherein D isone of the six carbocyclic moieties:

E-C ll Q H or wherein O, is

wherein R and R are hydrogen or alkyl of one to 4 carbon atoms,inclusive, being the same or different; wherein R, is hydrogen, alkyl ofone to 12 carbon atoms, inclusive, cycloalkyl of 3 to l0 carbon atoms,inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenylsubstituted with one, 2, or 3 chloro or alkyl or one to 4 carbon atoms,inclusive; wherein R is hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro; wherein R is hydrogen or fluoro, with the provisothat R is fluoro only when R,-, is hydrogen or to 4 carbon atoms,inclusive. being the same or different with the proviso that no morethan one of R R,. and R is alkyl; and wherein R is (1) --C H2 -CHa or(5) gills with the proviso that R is only when E is wherein C,,H isaikyleneof one to 9 carbon atoms, inclusive, with one to 5 carbon atoms,inclusive, in the chain between -CR,,R,,- and terminal methyl; whereinR,, and R are hydrogen, alkyl of one to 4 carbon atoms, inclusive, orfluoro, being the same or different, with the proviso that R is fluoroonly when R,, is hydrogen or fluoro; wherein T is alkyl of one to 4carbon atoms, inclusive, fluoro, chloro, trifluoromethyl. or ()R mwherein R is hydrogen or alkyl of one to 4 carbon atoms, inclusive, andsis zero, one, 2 or 3, with the proviso that not more than two T's areother than alkyl; and wherein Z represents an oxa atom (-0) or C H-wherein C,H is a valence bond or alkylene of one to 9 carbon atoms,inclusive, substituted with zero, one, or 2 fluoro. with one to 6 carbonatoms, inclusive, between CR,,R,,- and the ring.

For example, 5-oxa-PGE,, one of the novel compounds of this invention,is represented by the formula:

'\/ W coon Vlll HO H OH HO H 6H 5-Oxa-l9,20-dinor-PGE,, in which thealkylterminated side chain has only six carbon atoms, is represented bythe formula:

S-Oxa-l3,l4-dihydro-PGE,, in which the normal C ',C CH=CH-vmoiety isreplaced by +CH- -CH is represented by the formula:

Some of the novel prostaglandin analogs of this invention have alkyl orfluoro suhstituents on the side chains. Others of the novelprostaglandin analogs of this invention have phenyl andsubstituted-phenyl substitution. For example. l6,1-dimethyl-Swma-PGE isrepresented by the formula:

5-Oxa-l 7-phenyl-l 8,19,20-trinor-PGE isv represented by the formula;

Also included among the novel prostaglandin analogs of this inventionare l5-alkoxy and l6-phenoxy ethers. 5-oxa-PGE,. l5-methyl ether isrepresented by the formula 10 vl6-Methyl-5-oxa-lb-phenoxy-l8,l9,20-trinor-PGE,, is represented by theformula Also included within the novel prostaglandin analogs of thisinvention are the corresponding PGF. PGA, PGB. ll-deoxy-PGE, andll-deoxy-PGF compounds. For example. S-oxa-PGF is represented by theformula XVII S-Oxa-PGA is represented by the formula XIX 5 -Oxa ll-deoxy-PGF, is represented by the formula The names of these examplesof formulas Vll to XX are typical of the names used'hereinafter for thenovel compounds of this invention. These names can better be understoodby reference to the structure and numbering system of prostanoic acid(Formula I, above). That formula has seven carbon atoms in thecarboxyterminated chain and eight carbon atoms in the methylterminatedchain. In these names, 5oxa" indicates an oxa oxygen (-0-) in place ofthe C-5 methylene of the prostaglandin compound.

The use of nor. dinor", or *trinor" in the names of the novel compoundsof this invention indicates the absence ofone. twt or three of the chaincarbon atoms and the attached hydrogen atoms. The number or numbers infront of nor. dinor, or trinor indicate which of the original prostanoicacid carbon atoms are missing in the named compound. It is understoodthat the ter- 11 minal carbon atom in a chain carries its normalcomplement of hydrogen atoms. Formulas X. XlV: and XVl, above.illustrate this system of nomenclature.

In the name of the formula-IX example, ZO-methyl indicates that a methylgroup replaces a hydrogen on 5 C-2() so that the chain is extended byone carbon atom.

Where there is substitution in the side chains. for instance alkyl.fluoro, or phenyl, the points ofattachmcnt to the side chains areindicated in the conventional manner, following the atomic numbering ofthe prosto tanoic acid skeleton. Formulas XIII and XIV. above, areillustrative.

In the names of these compounds. l 7,l8-dehydro- PGE," indicates thatthere is one less hydrogen on each of the C17 and C-l8 carbon atoms thanin the PGE 15 structure, so that the normal CH CH moiety is replacedwith CH=CH. 13,-.14-Dihydro-PGE," in the name indicates one morehydrogen on each of the C-l3 and C-l4 carbon atoms than in the PGEstructure, so that the CH=CH- moiety is replaced with ---CH CH In thesenames, ll-deoxy" indicates that the hydroxyl at C-ll is replaced withhydrogen. Formulas X, Xll, XIX. and XX, above, are illustrative.

lncluded in the novel compounds of this invention are the lS-epimers.Where the C-l5 configuration is 25 the same as that of the naturalprostaglandin PGE, identified as 5 configuration, the name will notidentify the configuration at C-l5. If the lS-epimer is intended, thename will include IS-beta" or "l5(R)".

The presently described acids and esters of the 5-oxa prostaglandinanalogs include compounds of the following formulas which are intendedto represent the same optically form as of the naturally occurringprostaglandins. There are also included the racemic compoundsrepresented by each respective formula and the 35 mirror image thereof.There are also included the alkanoates of two to 8 carbon atoms,inclusive and also the pharmacologically acceptable salts thereof when Ris hydrogen.

Hd ll R Formulas XXI to XXVI represent S-oxa compounds of the PGE and ll-deoxy-PGE types. Formulas XXVII to XXXII represent -oxa compounds ofthe PGF and I l-deoxy-PGF types. Formulas XXXIII to XXXV represent 5-oxacompounds of the PGA type. Formulas XXXVI to XXXVIII represent S-oxacompounds of the PCB type.

Formulas XXXIX to LXII represent 5-oxa compounds in which there is abenzene or aromatic nucleus. Formulas XXXIX to XLVI represent S-oxacompounds of the PGE and I l-deoxy-PGE types. Formulas XLVII to LIVrepresent S-oxa compounds of the PGF and I l-deoxy-PGF types. FormulasLV to LVIII represent 5-oxa compounds of the PGA type. Formulas LIX toLXII represent 5-oxa compounds of the P68 type.

In formulas XXI to LXII, inclusive, C,,H is alkylene of one to 9 carbonatoms, inclusive, with one to 5 carbon atoms, inclusive, in the chainbetween -CR,,R and terminal methyl. CJHZ] is a valence bond or alkyleneof one to 9 carbon atoms, inclusive, substituted with zero, one, or 2fluoro, with one to 6 carbon atoms, inclusive. between --CR,,R,, and thering. 0, is

wherein R and R are hydrogen or alkyl of one to 4 carbon atoms,inclusive. being the same or different. R, is hydrogen, alkyl of one tol2 carbon atoms, inclusive. cycloalkyl of 3 to II) carbon atoms,inclusive, aralkyl of 7 to 12 carbon atoms. inclusive, phenyl, or phenylsubstituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms,inclusive. R R,,, and R are hydrogen, alkyl of one to 4 carbon atoms,inclusive. or fluoro, being the same or different, with the proviso thatR,, is fluoro only when R,, is hydrogen or fluoro and with the furtherproviso that neither Ri, nor R are fluoro in the compounds containingthe moiety represented by formulas XLIIl-XLVI, Ll-LIV, LVII, LVIII, LXI,and LXII above. R is hydrogen or fluoro, with the proviso that R isfluoro only when R is hydrogen or fluoro. R, and R,-, are hydrogen oralkyl of one to 4 carbon atoms, inclusive, being the same or different,with the proviso that no more than one of R R and R is alkyl. T is alkylof one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, orOR,,,, wherein Rm is hydrogen or alkyl of one to 4 carbon atoms,inclusive, and s is zero, one, 2, or 3, with the proviso that not morethan two Ts are other than alkyl. The indicates attachment of hydroxylto the ring in alpha or beta configuration.

In formulas XXI to LXII wherein there is a C C ethylenic group, forexample formulas XXI and XXII, that ethylenic group is in transconfiguration. In formulas XXI to LXII wherein there is a C -C ethylenicgroup, for example formulas XXII and XXV, that et'hylenic group is incis configuration.

Those PGF-type compounds represented by formulas XXVII-XXXII andXLVII-LIV wherein the C-9 hydroxyl is attached to the cyclopentane ringwith a wavy 18 line include both PGF -and PGFB -type compounds.

Inn" of the compounds represented by formulas XXI-XXXV and XXXIX-LVIII,the carboxylterminated side chain is attached to the cyclopentane ringin alpha configuration and the other side chain is attached in betaconfiguration.

As in the case of formulas II to VI, formulas XXI to LXII wherein O, is

i.e. wherein the C-IS hydroxyl or ether group is attached to the sidechain in alpha configuration, are each intended to represent opticallyactive prostanoic acid derivatives with the same absolute configurationas PGE, obtained from mammalian tissues.

Also included within this invention are the IS-epimer compounds offormulas XXI to LXII wherein Q, is

These are identified hereinafter as l5-epi", I58, or 15(R compounds bythe appropriate prefix in the name. For example, IS-epi-S-oxa-PGE,identifies the IS-epimeric compound corresponding to the formula-VIIIexample above except that it has the beta configuration atC-IS insteadof the natural alpha configuration of 5-oxa-PGE As is known in the artR" and S designation depends on the neighboring substituents. See R. S.Cahn, J. Chem. Ed. 41, I16 I964).

Included with this invention are both optically active enantiomorphsi.e. not only that isomer having the natural configuration, asrepresented by the formula herein, but also its enantiomer asrepresented by the mirror image of that formula, and also the racemiccompound, comprising both isomers. The racemic compound is properlyrepresented by two formulas, one as drawn herein and the other as itsmirror image. Such a racemic compound is designated herein by the prefixracemic (racor dl-) before its name; when that prefix is absent, theintent is to designate an optically active compound represented by theappropriate formula XXI to LXII. For convenience in the chartshereinjonly a single structural formula is used, for example in Chart B,to define not only the optically active form but also the racemiccompound which generally undergoes the same reactions.

With regard to formulas XXI to LXII, examples of alkyl of one to 4carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomericforms thereof. Examples of alkyl of one to l2 carbon atoms, inclusive,are those given above, and pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, dodecyl, and isomeric forms thereof. Examples of cycloalkyl of3 to 10 carbon atoms, inclusive, which includes alkyl-substitutedcycloalkyl, are cyclopropyl, Z-methylcyclopropyl,2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl,cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2.3,4-triethylcyclobutyl, cyclopentyl, 2,Z-dimethylcyclopentyl,Z-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tertbutylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl. cyclooctyl, cyclononyl, and

of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbonatoms, inclusive, are (o-, m-, or p- )chlorophenyl, 2,4-dichlorphenyl,2,4,6-

trichlorophenyl, (o-, m-, or p-)tolyl, p-ethylphenyl, ptert-butylphenyl,2,5-dimethylphenyl, 4-chloro-2- methylphenyl, and2,4-dichloro-3methylphenyl.

Examples of alkylene of one to 9 carbon atoms, inclusive, with one tocarbon atoms inclusive, in the chain, within the scope of C,,H asdefined above, are methylene, ethylene, trimethylene, tetramethylene,and pentamethylene, and those alkylene with one or more alkylsubstituents on one or more carbon atoms Examples of as defined aboveare phenyl, (o-, m-, or p-)tolyl, (o-, m-, or p-)ethylphenyl, (o-, m-,or p-)propylphenyl, (o-, m-, or p-)butylphenyl, (o-, m-, orp-)isobutylphenyl, (0-, m-, or p-)tert-butylphenyl, 2,3-xylyl,2,4-xylyl, 2,5xylyl, 2,6-xylyl, 3,4-xylyl, 2,6-diethylphenyl, 2-ethyl-p-tolyl, 4-ethyl-o-tolyl, S-ethyl-m-tolyl, 2-propyl- (o-, m-, orp-)tolyl, 4-butyl-m-tolyl, o-tert-butyl-mtolyl, 4-isopyropyl-2,6-xylyl,3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, 2-fluoro-(o-, m-,or p-)t0lyl, 4-

fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5- )difluorophenyl, (o-,m-, or p-)-chlorophenyl, 2- c.hloro-p-tolyl, (3-, 4-, 5-, or6-)chloro-o-tolyl,

4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4chloro-3,5-xylyl,(2.3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5- )dichlorophenyl,4-chloro-3-fluorophenyl, (3-, or 4- )chloro-Z-fluorophenyl, a, a,oz-trifluoro-(o-, m-, or p- )-tolyl, (o-, m-, or p-)methoxyphenyl, (o-,m-, or p- )ethoxyphenyl, (4- or 5-)chloro-2-methoxyphenyl, and2,4-dichloro-(5- or 6-)methoxyphenyl.

The novel formula XXl-to-LXll compounds and the racemic compounds ofthis invention each cause the biological responses described above forthe PGE, PGF PGFB and PGA compounds, respectively,

and each of these novel compounds is accordingly useful for theabove-described corresponding purposes, and is used for those purposesin the same manner as described above.

The known PGE, PGF PGF PGA and PGB compounds are all potent in causingmultiple biological responses even at low doses. For example, PGE. andPGE both cause vasodepression and smooth muscle stimulation at the sametime they exert antilipolytic activity. Moreover, for many applications,these known prostaglandins have an inconveniently short duration ofbiological activity. In striking contrast, the novel prostaglandinanalogs of formulas XXl-to-LXll and the corresponding racemic compoundsare substantially more specific with regard to potency in causingprostaglandin-like biological responses, and have a substantially longerduration of biological activity. Therefore, each of these novelprostaglandin analogs is surprisingly and unexpectedly more useful thanone of the corresponding above-mentioned known prostaglandins for atleast one of the pharmacological purposes indicated above for thelatter, because it has a different and narrower spectrum of biologicalpotency than the known prostaglandin, and therefore is more specific inits activity and causes smaller and fewer undesired side effects thanwhen the known prostaglandin is used for the same purpose. Moreover,because of its prolonged activity, fewer and smaller doses of the novelprostaglandin analog can frequently be used to attain the desiredresult.

Because of their unique chemical structure, the novel ll-deoxy-PGE andll-deoxy-PGF analogs of this invention of formulas XXIV-XXVI, XXX-XXX",XLl, XLll, XLV, XLVl, XLlX, L, Llll, and LIV are less sensitive tochemical change than the prostaglandins and enjoy increased chemicalstability and longer shelf life.

To obtain the optimum combination of biological response specificity,potency, and duration of activity, certain compounds within the scope offormulas XXI- to-LXll are preferred. With reference to the definitionsgiven above, it is preferred that C,,H be straight chain of one to 5carbon atoms, inclusive. It is especially preferred that C,,H betrimethylene. lt is further preferred that Q, be

It is also preferred that the sum of the carbon atoms in R and R whenalkyl, be not greater than 7, and that the sum of the carbon atoms in RR R,,, and R taken together is not greater than 7. Another preference isthat if one or more of R R R R or R is alkyl, that it be methyl orethyl. It is especially preferred that if R,

or R is alkyl that it be methyl.

ln compounds XXXlX-to-LXll, it is preferred that C H be straight chainof one to 4 carbon atoms, inclusive. It is especially preferred thatCJHQJ be methylene,

It is further preferred that ifT is alkyl that it be methyl,

invention, especially the preferred compounds defined hereinabove,compared with the known prostaglandins, is that these novel compoundsare administered effectively orally, sublingually, intravaginally,buccally, or

rectally, in addition to usual intravenous. intramuscular, orsubcutaneoous injection or infusion methods indicated above for the usesofthe known prostaglandins. These qualities are advantageous becausethey facilitate maintaining uniform levels of these compounds in thebody with fewer, shorter. or smaller doses. and make possibleself-administration by the patient.

The S-oxa prostaglandin analogs encompassed by formulas XXl-to-LXllincluding their alkanoates, are used for the purposes described above inthe free acid form, in ester form, or in pharmacologically acceptablesalt form. When the ester form is used, the ester is any of those withinthe above definition of R,. However, it is preferred that the ester bealkyl of one to 12 carbon atoms, inclusive. Of those alkyl, methyl andethyl are especially preferred for optimum absorption of the compound bythe body or experimental animal system; and straight-chain octyl, nonyl,decyl, undecyl, and dodecyl are especially preferred for prolongedactivity in the body or experimental animal.

Pharmocologically acceptable salts of these formula XXl-to-LXIIcompounds useful for the purposes described above are those withpharmacologically acceptable metal cations. ammonium, amine cations. orquaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium. sodium, and potassium. and from the alkalineearth metals. e.g.. magnesium and calcium. although cationic forms ofother metals. e.g., aluminum, zinc. and iron are Within the scope ofthis invention.

Pharmacologically acceptable amine cations are those derived fromprimary. secondary. or tertiary amines. Examples of suitable amines aremethylamine. dimethylamine. trimethylamine. ethylamine. dibutylamine.triisopropylamine. Nmethylhexylamine, decylamine, dodecylamine,allylamine. crotylamine. cyclopentylamine, dicyclohexylamine,benzylamine. dibenzylamine, a-phenylethylamine, B-phenylethylamine,ethylenediamine, diethylenetriamine. and like aliphatic. cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine. and lower-alkyl derivatives thereof, e.g.,l-methylpiperidine, ethylmorpholine, l-isopropylpyrrolidine, 2-methylpyrrolidine, l,4-dimethylpiperazine, 2

methylpiperidine, and the like, as well as amines containingwater-solubilizing or hydrophilic groups, e.g., mono-, di-. andtriethanolamine, ethyldiethanolamine, N-butylethanolamine,Z-amino-l-butanol, 2-amino-2- ethyl-l.3-propanediol.Z-amino-Z-methyl-l-propanol. tris(hydroxymethyl)aminomethane. N-phenylethanolamine, N-(p'tert-amylphenyl)diethanolamine. galactamine,N-methylglycamine, N- methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium.benzyltrimethylammonium, phenyltriethylammonium, and the like.

The compounds encompassed by formulas XXI-to- LXlI are used for thepurposes described above in free hydroxy form or also in the formwherein the hydroxy moities are transformed to lower alkanoate moieties,e.g., -OH to OCOCH Examples of lower alkanoate moieties are acetoxy,propionyloxy, butyryloxy,

valeryloxy. hexanoyloxy. heptanoyloxy, octanoyloxy, and branched chainalkanoyloxy isomers of those moieties. Especially preferred among thesealkanoates for the above described purposes are the acetoxy compounds.These free hydroxy and alkanoyloxy compounds are used as free acid, asesters. and in salt form all as described above.

As discussed above, the compounds offormulas XXlto-LXll are administeredin various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action. For intravenous injection or infusion, sterileaqueous isotonic solutions are preferred. For that purpose, it ispreferred because of increased water solubility that R in the formulaXXl-to-LXII compound be hydrogen or a pharmacologically acceptablecation. For subcutaneous or intramuscular injection, sterile solutionsor suspensions of the acid, salt, or ester form in aqueous ornon-aqueous media are used. Tablets, capsules, and liquid preparationssuch as syrups, elixirs, and simple solutions, with the usualpharmaceutical carriers. are used for oral sublingual administration.For rectal or vaginal administration, suppositories prepared as known inthe art are used. For tissue implants, a sterile tablet or siliconerubber capsule or other object containing or impregnated with thesubstance is used.

The S-oxa prostaglandin analogs encompassed by formulas XXl through LXllare produced by the reactions and procedures described and exemplifiedhereinafter.

Reference to Charts A and B herein will make clear the process stepsstarting in .Chart A with the iodolactone of formula LXlll to providethe lactol of formula LXXll. and in Chart B, the transformation of themore general lactone of formula LXXlIl to yield the S-oxa PGFtypecompounds of formula LXXVI.

CHART A O at Q LX l uzocu3 dH LXI CH OC s V different, with the provisothat r" is fluoro only when R is hydrogen or fluoro. R is l l Tls -lC-CHg -CH OF -f-Z- wherein C.,H is alkylene of one to 9 carbon atoms.inclusive. with one to carbon atoms. inclusive. in the chain betweenCR,,R,,and terminal methyl; wherein R" and R1, are as defined above,wherein T is alkyl of one to 4 carbon atoms, inclusive. fluoro. chloro,trifiuoromethyl, or -ORm, wherein R10 is hydrogen or alkyl of one to 4carbon atoms. inclusive. and s is zero, one, 2, or 3. with the provisothat not more than two Ts are other than alkyl; and wherein Z representsan oxa atom (-O or C H wherein C H is a valence bond or alkylene of oneto 9 carbon atoms. inclusive, substituted with zero, one, or 2 fluoro.with one to 6 carbon atoms, inclusive between CR,.R,,. and the ring. Ris coca (2) wherein R is alkyl of one to 4 carbon atoms, inclusive;

ld (R... 19

wherein R and d are as defined above; or (4) acetyl. Use of acetyl orp-phenylbenzoyl is known in the art. See Corely et al.. J. Am. Chem.Soc. 93, 149i (197i Likewise in Chart A. R is a blocking group", whichis defined as any group which replaces hydrogen of the hydroxyl groups,which is not attacked by nor is reactive to the reagents used in therespective transformations to the extent that the hydroxyl group is. andwhich is subsequently replaceable by hydrogen at a later stage in thepreparation of the prostaglandin-like products. Several blocking groupsare known in the art, e.g. tetrahydropyranyl and substitutedtetrahydropyranyl (see Corey. Proceedings of the Robert A. WelchFoundation Conferences on Chemical Research. Xll, Organic Synthesis. pp.51-79 (1969)). Those blocking groups which have been found usefulinclude (a) tetrahydropyranyl; (b) tetrahydrofuranyl; or (c) a group ofthe formula wherein R is alkyl of one to 18 carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkylof one to 4 carbon atoms, inclusive, wherein R and R are the same ordifferent, being hydrogen, alkyl of one to 4 carbon atoms, inclusive,phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbonatoms, inclusive. or, when R and R are taken together, (CH )a -or (CH)b-O-(CH )cwherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2or 3 with the proviso that b plus c is 2, 3 or 4, and wherein R24 ishydrogen or phenyl.

Further in Chart A, 0 is either wherein R is a blocking group as definedabove, and indicates attachment of hydroxyl to the ring in alpha or betaconfiguration.

The iodolactone of formula LXlll is known in the art. See for example E..1. Corey et al., J. Am. Chem. Soc. 91, 5675 (1969) and 92, 397 (1970).It is available in either racemic or optically active or form. Forracemic products, the racemic form is used. For optically activeproducts having the same configuration as the naturally occurringprostaglandins, the laevorotatory (7-) form is used.

in preparing the formula-LXIV compound by replacing the hydrogen of thehydroxyl group in the 4- position with the acyl group R methods known inthe art are used. Thus. an aromatic acid of the formula R OH. wherein Ris as defined above, for example benzoic acid, is reacted with theformula-LXlll compound in the presence of a dehydrating agent, e.g.sulfuric acid, zinc chloride, or phosphoryl chloride; or an anhydride ofthe aromatic acid of the formula (R 9 0, for example benzoic anhydride,is used.

Preferably. however, an acyl halide, e.g. R Cl, for example benzoylchloride. is reacted with the formula- LXlll compound in the presence ofa hydrogen chloride-scavenger, e.g. a tertiary amine such as pyridine.triethylamine, and thelike. The reaction is carried out under a varietyof conditions using procedures generally known in the art. Generally,mild conditions are employed, e.g. 20-60 C., contacting the reactants ina liquid medium, e.g. excess pyridine or an inert solvent such asbenzene, toluene or chloroform. The acylating agent is used either instoichiometric amount or in excess.

As C. B. of reagents providing R for the purposes of this invention, thefollowing are available as acids (R OH). anhydrides ((R, or acylchlorides (R cl); b l; b ti d b l, (2- 3- 6} The formula-LXIX compoundis obtained as a mix- 4-lmethylbenzoyl, (2-, 3-, or 4-)ethylbenzoyl,(2-, 3-, ture of alpha and beta hydroxy isomers by reduction of or 4 ilb L 2- 3. or 4 LXVlll. For this reduction, use is made of any of the blb L 2,4-dim thylbenz yl 35. known ketonic carbonyl reducing agentswhich do not dimethylbenzoyl, Z-isopropyltoluyl, 2,4 6- 5 reduce esteror acid groups or carbon-carbon double i h m l penmmcthymenmfl h 2.bonds when the latter is undesirable. Examples ofthose 3-, or 4-)toluyl.2-. 3-, or 4-phcnethylbenzoyl, 2., 3., m are the metal lmrohydrides.especially sodium, potas- 4 nilmhcnmy| 2 25- m 3 5 i ,h sium, and zincborohydrides. lithium (tri-tert-lmtoxy) 4 5 2 m p 2 aluminum hydride,metal trialkoxy borohydridcs. e.g., phenmhymenzoyL 3- i 2 h mono. tosodium trimethoxyborohydride. lithium borohydride. is-termed phthamyLdusobutyl aluminum hydride, and when carbon-carbon H II isophthaloyl,e.g. ll or Or -m p y n Substituted naphthoyl, e.g. double bond reductionis not a problem, the boranes, (2-, 3-, 4-, 4-, 6-, or7-)-methyl-l-naphthoyl. (2- or e.g.,disiamylborane(bis-3-methyl-2-butylborane). For 4-) hy1-l-n ph h yl. -i0pr pyl-l-n phthoyl. production of natural-configuration prostaglandins,the 4,5-dimethyl-1-naphthoyl. 6-is0pr0py -m t y alpha form of theformula-LXIX compound is sepanaphthoyh y p y w or rated from the betaisomer by silica gel chromatogranitro-l-naphthoyl,4,5-dinitro-l-napnoyl, (3-. 4-. 6-, 7- hy using methods known in theart.

or 8-)methyl-l-naphthoyl,4-ethyl-2-naphthoyl.and(5- The formula-LXXcompound is then obtained by -)flitr0-2-naphthoy|. There may beemployed. deacylation of LXlX with an alkali metal carbonate, fortherefore. benzoyl chloride, 4-.nitrobcnzoyl chloride. example potassiumcarbonate in methanol at about 25 3.5-dinitrobenzoyl chloride, and thelike. i.e. R,. ,C| C,

compounds corresponding to the above R groups. lf The fQrmUIa-LXXIlactone is obtained by replacing the acyl chloride is not available, itis made from the the hydrogen atoms of the hydroxyl groups of LXXcorresponding acid and phosphorus pentachloride as is with a blockinggroup. When the blocking group is tetkn0 n in the a tit iS P ed a eRIZOH rahydropyranyl or tetrahydrofuranyl, the appropriate lZ)2 a izreactant does not have y. hihdefreagent, e.g. 2.3-dihydropyran or2,3-dihydrofuran, is ing substituents, e.g. tert-butyl, on both of thering carused in an inert solvent such as dichloromethane, in the honatoms adjacent to the carbonyl attaching-site. re en e of an a idcondensing agent such as p-tol- The fOI'mUIa-L mp n is heXt bta ne y euenesulfonic acid or pyridine hydrochloride. The reaodination of LXlVusing a reagent which does not react gem is used in slight excess,preferably 1.0 to 1.2 times with the lacwhe ring or the rz moiety, 'g-Zinc dust 4O theory. The reaction is carried out at about 20-50 C.sodium hydride, hydrazine-palladium, hydrogen and wh th bl king group isof the formula Raney nickel or platinum, and the like. Especiallypreferred is tributyltin hydride in benzene at about 25 C. i with2,2-azobis-(Z-methylpropionitrile) as initiator. Ra 1- 22 2s 24,

The formula-LXVI compound is obtained by de- V I r methylation of LXVwith a reagent that does not attack as defined above, the appropriatereag eifi is a vinyl the OR moiety, for example boron tribromide ortriether, e.g. isobutyl vinyl ether or any vinyl ether of the chloride.The reaction is carried out preferably in an formula R -O-C(R )=CR Rwherein R R R inert solvent at about ()5 C. and R are defined above; oran unsaturated cyclic The formula-LXVll compound is obtained by oxidaorheterocyclic compound, e.g. l-cyclohex-l-yl methyl tion of the CH OH ofLXVl to --CHO, avoiding deether composition of the lactone ring. Usefulfor this purpose are dichromate-sulfuric acid, Jones reagent, lead tetr-CH aacetate, and the like. Expecially preferred is Collins U reagent(pyridine-CrOo) at about 0-l0 C.

The formula-LXVlll compound is obtained by Witting alkylation of LXVll,using the sodio derivative of or 5,6-dihydro-4-methoxy-ZH-pyran anappropriate dimethyl 2-oxoalkylphosphonate within the scope of CHSO ,5See C.B. Reese et al., J. Am. Chem. Soc. 89, 3366 wherein RR. R and Rare as defined above. The tran (1967). The reaction conditions for suchvinyl ethers enone lactone is obtained stereo-specifically (see D. H.and unsaturates are similar to those for dihydropyran Wadsworth et al,J. Org. Chem. Vol 30, p. 680 1965)). b v

The formula-LXX" lactol is obtained on reduction of lactone LXXl withoutreducing the ethylenic group. For this purpose, diisobutylaluminumhydride is used as known in the art. The reduction is preferably done at60 to 70 C.

The stereochemistry of the side chain is preserved in transforming LXlXto LXX to LXXl to LXXll. For example a 3-alpha compound LXIX yields a3-alpha com pound LXXll.

The preparation of lactol LXXll with specific embodiments of R,,, R Rand R,,-, was reported by E. J. Corey et al., first in racemic form inJ. Am. Chem. Soc. 91, 5675 (1969) and later in optically active form inJ. Am. Chem. Soc. 92, 397 (1970).

Referring to Chart B, there are shown the novel steps of this inventionwhereby lactol LXXlll is transformed to a S-oxa PGFa'type product LXXVl.

in Chart B, the terms R R R R R 02, Q3. and have the same meaning as inChart A. R includes 5 Us and -g-Z- as defined above and also the groupIntermediate lactol LXXlll includes lactol LXXll of Chart A and alsolactols of the formula CXl For the compound wherein R istetrahydropyranyl, see Corey et al., J. Am. Chem. Soc. 93, I490 (l97lPreparation of similar formula-LXXlll compounds is by known methods.

Alcohol LXXlV is obtained on reduction of lactol LXXIII, for examplewith aqueous methanolic or ethanolic sodium borohydride. Alternativelyand preferably, alcohol LXXIV is obtained by one-step reduction of aformula-LXXI lactone, for example with lithium aluminum hydride ordiisobutylaluminum hydride at -35 C.

For preparing the formula-LXXV compound, a Williamson synthesis isemployed. For example, the formula-LXXIV alcohol is condensed with ahalobutyrate or appropriate haloester within the scope of H H R whereinHal is chloro, bromo, or iodo and R R R and R are as defined above.Normally the reaction is done in the presence of a base such asn-butyllithium, phenyllithium, triphenylmethyllithium, sodium hydride,or potassium t-butoxide. Alternatively and preferably, anortho-4-bromo-butyrate within the scope of 30 ring -g 2e)s wherein R isalkyl of one to 3 carbon atoms, inclusive, and R R R and R areas'defined above, is employed. Such reagents are available or preparedby methods known in the art, for example from the appropriatehalonitrile by way of the corresponding imino ester hydrohalide asillustrated hereinafter. The condensation is conveniently run in asolvent such tetrahydrofuran or dimethyl sulfoxide, or especially if anorganolithium compound is employed, preferably in dimethyl formamide orhexamethylphosphoramide. The reaction proceeds smoothly at -20 to 50 C.,but is preferably done at about 25 C. for convenience. Fol lowing thecondensation, the formula-LXXV compound is obtained by methods known inthe art. for example by hydrolysis in cold dilute mineral acid.

The 5 oxa PGF -type product LXXVl is obtained from the LXXV intermediateby hydrolysis of the blocking groups for example in dilute acetic acid,aqueous citric acid, or aqueous phosphoric acidtetrahydrofuran.

Referring to Chart C, there is shown the transformation of the LXXVintermediates of Chart B to the formula-LXXV" PGE-type products or theformula- LXXVlll PGFfi In Chart C, the terms R R R,, R R,,,, R 0 and 0,,are as defined above; R is hydrogen, alkyl of one to [2 carbon atoms,inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7to 12 carbon atoms, inclusive, phenyl, or phenylsubstituted with one, 2,or 3 chloro or alkyl of one to 4 carbon atoms, inclusive. The steps bywhich LXXV is transformed to LXXVll depends on whether R is methyl orother group or hydrogen. If R, is methyl, the procedure is simply tooxidize the C-9 position and then replace the was and -LXXlX PGF -typeproducts.

blocking groups with hydrogen.

Oxidation reagents useful for this tranformation are known in the art. Auseful reagent for this purpose is the Jones reagent, i.e., acidifiedchromic acid. See J. Chem. Soc. 39 (1946). A slight excess beyond theamount necessary to oxidize the C-9 secondary hydroxy groups of theformula-LXXV reactant is used. Acetone is a suitable diluent for thispurpose. Reaction temperatures at least as low as about C. should beused. Preferred reaction temperatures are in the range 0 to 50 C. Anespecially useful reagent for this purpose is the Collins reagent, i.e.chromium trioxide in pyridine. See J. C. Collins et al., TetrahedronLett., 3363 (I968). Dichloromethane is a suitable diluent for thispurpose. Reaction temperatures of below 30 C. should be used. Preferredreaction temperatures are in the range 0 to +30 C. The oxidationproceeds rapidly and is usually complete in about to minutes.

Examples of other oxidation reagents useful for this transformation aresilver carbonate on Cclite (Chem. Commun. I102 (1969)). mixtures ofchromium trioxide and pyridine J. Am. Chem. Soc. 75. 422 (I953). andTetrahedron, I8, 1351 (1962)). t-butylchromate in pyridine (Biochem..l., 84, 195 (1962)), mixtures of sulfur trioxide in pryidine anddimethylsulfoxide (J. Am. Chem. Soc. 89, 5505 (1967)), and mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87,5661 (1965)).

The formula-LXXVll S-oxa PGE-type compound is then obtained byhydrolysis of the blocking groups, for example in dilute acetic acid;

If R, in the desired formula-LXXVll product is to be hydrogen or adifferent group than methyl, the formula-LXXV intermediate is hydrolyzedor saponified under alkaline conditions by the usual known proceduresand recovered in the free acid form. This acid intermediate is eithersubjected to the oxidation and hydrolysis steps above to yield LXXVll inacid form (R, is hydrogen) or it is converted to the desired ester, forexample with a diazoalkane or by other methods de' scribed herein, andthen transformed by oxidation and hydrolysis to product LXXVll.

Continuing with Chart C, the formula-LXXVlll PGFB -type products areobtained by carbonyl reduction of the corresponding formula-LXXVll PGE-type compounds. There are obtained in the same reaction thecorresponding formula-LXXlX PGF -type compounds. For example, carbonylreduction of S-oxa- PGE, gives a mixture of 5-oxaPGF and 5-oxa- PGF,

These ring carbonyl reductions are carried out by methods known in theart for ring carbonyl reductions of known prostanoic acid derivatives.See, for example. Bergstrom et al., Arkiv Kemi I9, 563 (1963). Acta.Chem. Scand. 16, 969 (1962). and British Specification No. 1,097,533.Any reducing agent is used which does not react with carbon-carbondouble bonds or ester groups. Preferred reagents are lithium(tri-tertbutoxy)aluminum hydride, the metal borohydrides. especiallysodium, potassium and zinc borohydrides, and the metal trialkoxyborohydrides, e.g., sodium trimethox'yborohydride. The mixtures of alphaand beta hydroxy reduction products are separated into the individualalpha and beta isomers by methods known in the art for the separation ofanalogous pairs of known isomeric prostanoic acid derivatives. See, forexample. Bergstrom et al., cited above, Granstrom et al., J. Biol. Chem.240.457 (1965), and Green et al., J. Lipid Research 5, 117 (I964).Especially preferred as separation methods are column chromatography.partition chromatographic procedures, both normal and reversed phase,preparative thin layer chromatography,

. and countercurrent distribution procedures.

Referring to Chart D, there is shown the transformation oflactone LXXXto 5-oxa l5-alkyl ether PGF-type products of formula LXXXlll. In ChartD, R R R R R R Q and have the same meanings as above. 0 is eitherwherein R is alkyl of one to 4 carbon atoms, inclusive. The startingmaterials are available from the steps of Chart A above or are readilyavailable by methods known in the art.

The formula-LXXX] compound is prepared by alkylation of the side-chainhydroxy of the formula-LXXX compound thereby replacing hydroxy with the-OR, moiety. For this purpose. diazoalkanes may be employed, preferablyin the presence ofa Lewis acid, e.g. boron trifluoride etherate,aluminum chloride, or fluoboric acid. When R is methyl, diazomethane isused. See Fieser et al., "Reagents for Organic Synthesis, John Wiley andSons, lnc., N.Y. (l967), p. 191. Other -OR, groups are formed by usingthe corresponding diazoalkane. For example diazoethane and diazobutaneyield OC H,-, and OC H,, respectively. The reaction is carried out bymixing a solution of the diazoalkane in a suitable inert solvent,preferably ethyl ether,

CHART D o 9% I LXXX CHART D Continued LXXXl LXXXl 1 LXXXlll with theformula-LXXX compound. Generally the reaction proceeds at about 25 C.Diazoalkanes are known in the art or can be prepared by methods known inthe art. See, for example, Organic Reactions, John Wiley and Sons, Inc.,N.Y. Vol. 8, pp. 389-394 (1954).

Another method for the alkylation of the side chain hydroxy is byreaction with an alcohol in the presence of boron trifluoride etherate.Thus. methanol and boron trifluoride etherate yield the methyl etherwherein R is methyl. The reaction is done at about 25 C. and isconveniently followed with thin layer chromatography (TLC).

Another method for the alkylation of the side-chain hydroxy is by thereaction of an alkyl halide, e.g. methyl iodide. in the presence of ametal oxide or hydroxide, e.g. barium oxide, silver oxide, or bariumhydroxide. An inert solvent may be beneficial, for example benzene ordimethylformamide. The reactants are preferably stirred together andmaintained at temperatures of 25-75 C.

Still another method is by first converting the hydroxy to mesyloxy(i.e. methanesulfonate) or tosyloxy (i.e. toluenesulfonate) and thencetransforming the mesyloxy or tosyloxy to the OR moiety by reaction witha metal alkoxide, e.g. potassium tert-butoxide. The mesylate or tosylateis prepared by reaction of the formula-LXXX intermediate with eithermethanesulfonyl chloride or toluenesulfonyl chloride in pyridine.Thereafter. the mesylate or tosylate is mixed with the appropriatepotassium or sodium alkoxide in pyridine, the reaction proceedingsmoothly at about 25 C. an equivalent amount of the alkoxide based onthe mesylate is preferred to avoid side reactions. in this manner, theformula-LXXXI intermediate is prepared wherein R is normal alkyl.secondary alkyl. or tertiary alkyl of one to 5 carbon atoms. The methodis especially useful for tertiary alkyl substitutions for hydrogen. e.g.where R is tert-butyl or tert-pentyl.

The formula-LXXXII compound is then obtained in the conventional manner,for example by low temperature reduction with disobutylaluminum hydrideas discussed above for Chart A. The final 5-oxa l5-alkyl ether PGFproduct LXXXlll is obtained from either LXXXl or LXXXll by the samereactions and conditions discussed above for the steps of Chart B.

Referring to Chart E, there is shown the transformation of lactoneLXVlll to lactol LXXXVll useful for preparing 5-oxa-l5'alkyl-PG-typeproducts. In Chart E, R,,, R,,, R R R and are as defined above for ChartA. 0;, is either wherein R is alkyl of one to 4 carbon atoms, inclusive.

Q is either wherein R and R are as defined above.

For the starting material LXVlll refer to Chart A and the discussionpertaining thereto. Intermediate LXXXlV is obtained by replacing theside-chain 0x0 with Q,-, by a conventional Grignard reaction, employingR Mgl-lal. Next. the acyl group R is removed by hydrolysis and thehydrogen atoms of the hydroxyl groups are replaced with blocking groupsR following theprocedures of Chart A. Finally lactol LXXXVII is obtainedby reduction of lactone LXXXVI in the same manner discussed above forCharts A and D.

The l5-alkyl products of this invention are obtained LXXXlV u d l LXXXVCHART E-Continued i i l A LXXXVI 11 1 0 l R130 1&2 R9 l() HO L 0 t 15LXXXVII M11 R 30 QGRS Referring to Chart F, there is shown a convenientmetnod for obtaining the 5-oxa l5-alkyl products from corresponding5-oxa PGF-type compounds shown broadly by formula LXXXVlll. in chart F,R,, R R R R R R,,,, 0 and are as defined above. G is alkyl of one to 4carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive,phenyl, or phenyl substituted with one or 2 fluoro, chloro, or alkyl ofone to 4 carbon atoms, inclusive, and R is R, as defined above or silylof the formula-Si-(GM wherein G is as defined above. The various Gs of aSi(G) moiety are alike or different. For example, a -Si(G),-, can betrimethylsilyl, dimethyl(t-butyl)silyl, dimethylphenylsilyl, ormethylphenylbenzylsilyl. Examples of alkyl of one to 4 carbon atoms,inclusive, are methyl, ethyl, propyl, isopropyl, butyl isobutyl,sec-butyl, and tert-butyl. Examples of aralkyl of 7 to 12 carbon atoms,inclusive, are benzyl, phenethyl, a-phenylethyl, 3-phenylpropyl,a-naphthylmethyl, and Z-(B-naphthyUethyl. Examples of phenyl substitutedwith one or 2 fluoro, chloro, or alkyl of one to 4 carbon atoms,inclusive, are pchlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl, and2,4-dichloro-3-methylphenyl.

This method is well-known for preparing lS-alkyl CHART F Continuedprostaglandins. See South African Pat. No. 2482, May 3, 1972, or BelgianPat. No. 766,682, Derwent No. 721098.

The acids and esters of formula LXXXVlll, available herein by theprocesses of Charts B and C, are transformed to the correspondingintermediate lS-oxo acids and esters of formula LXXXIX, respectively, byoxidation with reagents such as2.3-dichloro-5,fi-dicyanol,4-benzoquinone, activated manganese dioxide,or nickel peroxide (see Fieser et al., Reagents for Organic Synthesis,"John Wiley & Sons, Inc., New York, N.Y., pp. 215, 637 and 731).

Continuing with Chart F, intermediate LXXXIX is transformed to a silylderivative of formula XC by procedures known in the art. See, forexample. Pierce. Silylation of Organic Compounds," Pierce Chemical Co.,Rockford, Illinois l968). Both hydroxy groups of the form ula-LXXXlXreactant are thereby transformed to -O-Si--(G);; moieties wherein G isas defined above, and sufficient of the silylating agent is used forthat purpose according to known procedures. When R. in theformula-LXXXIX intermediate is hydrogen, the COOH moiety thereby definedis usually transformed to -COO-Si-(G);;, additional silylating agentbeing used for this purpose. This latter transformation is aided byexcess silylating agent and prolonged treatment. When R in formulaLXXXlX is alkyl, then R in Formula XC will also be alkyl. The necessarysilylating agents for these transformations are known in the art or areprepared by methods known in the art. See, for example, Post, Siliconesand Other Organic Silicon Compounds, Reinhold Publishing Corp, New York,NY. (1949).

The intermediate silyl compound of formula XC is transformed to thefinal compounds of formula XCI XCII by first reacting the silyl compoundwith a Grignard reagent of the formula R MgHal wherein R is methyl orethyl, and Hal is chloro, bromo. or iodo. For this purpose, it ispreferred that Hal be bromo. This reaction is carried out by the usualprocedure for Grignard reactions, using diethyl ether as a reactionsolvent and saturated aqueous ammonium chloride solution to hydrolyzethe Grignard complex. The resulting disilyl or trisilyl tertiary alcoholis then hydrolyzed with water to remove the silyl groups. For thispurpose, it is advantageous to use a mixture of water and sufficient ofawater-miscible solvent, e.g., ethanol to give a homogenous reactionmixture. The hydrolysis is usually complete in 2 to 6 hours at 25 C.,and is preferably carried out in an atomosphere of an inert gas, e.g.,nitrogen or argon.

The mixture of 15-8 and l-R isomers obtained by this Grignard reactionand hydrolysis is separated by procedures known in the art forseparating mixtures of prostanoic acid derivatives, for example, bychromatography on neutral silica gel. In some instances, the lower alkylesters, especially the methyl esters of a pair method ofobtaining the5-oxal 5-alkyl-PGF-type compounds as l5-alkyl ethers. in Chart G, R,, RR R 5. m. R Q Q,-,, and are as defined above. O is either

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA
 2. A compound accordingto claim 1 wherein * is alpha.
 3. A compound according to claim 2wherein Q1 is
 4. A compound according to claim 3 wherein the sum of thecarbon atoms in R6, R7, R8, and R9 taken together is not greater than 7.5. A compound according to claim 4 wherein R3, R4, and R5 are eitherhydrogen or methyl, and one of R3, R4, and R5 is methyl.
 6. A compoundaccording to claim 4 wherein R2, R3, R4, and R5 are hydrogen.
 7. Acompound according to claim 6 wherein R6, R7, R8, and R9 are eitherhydrogen or methyl, and at least one of R6, R7, R8, and R9 is methyl. 8.A compound according to claim 7 wherein R6 is methyl.
 9. A compoundaccording to claim 7 wherein R7 is methyl.
 10. A compound according toclaim 7 wherein one or both of R8 and R9 are methyl.
 11. A compoundaccording to claim 6 wherein R6, R7, R8, and R9 are hydrogen.
 12. Acompound according to claim 11 wherein Z is oxa (-O-).
 13. A compoundaccording to claim 11 wherein Z is methylene.
 14. An optically activecompound according to claim
 13. 15. A compound according to claim 14wherein R1 is alkyl of one to 12 carbon atoms, inclusive. 16.5-oxa-17-phenyl-18,19,20-trinor-PGF1 , methyl ester, a compoundaccording to claim
 15. 17. A compound according to claim 14 wherein R1is hydrogen.
 18. A racemic compound according to claim
 13. 19. Acompound according to claim 2 wherein Q1 is
 20. A compound according toclaim 1 wherein * is beta.
 21. A compound according to claim 20 whereinQ1 is
 22. A compound according to claim 20 wherein Q1 is